GlaxoSmithKline Research and Development, Genetics Division, Stevenage, UK.
J Hepatol. 2011 Jun;54(6):1237-43. doi: 10.1016/j.jhep.2010.09.028. Epub 2011 Feb 12.
BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.
Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.
Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.
The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.
帕唑帕尼已被证明对晚期肾细胞癌（RCC）患者具有临床获益，且通常具有良好的耐受性。然而，通常会观察到转氨酶升高。这项两阶段研究旨在确定接受帕唑帕尼治疗的白人 RCC 患者中丙氨酸转氨酶（ALT）升高的遗传决定因素。
使用两项独立的临床研究的数据，研究了 282 个候选基因中 6852 个遗传多态性与治疗期间最大 ALT 水平之间的关联。
在对 115 例患者的探索性数据集进行检查的 282 个候选基因的 92 个多态性中，40 个基因的 92 个多态性与 ALT 升高显著相关（p<0.01）。两个标记物（rs2858996 和 rs707889）在 HFE 基因中，虽然尚未证实与血色素沉着症有关，但有证据表明存在复制。由于多次比较，有 12%的可能性是偶然发生的复制。这两个标记物显示出强烈的连锁不平衡（r（2）=0.99）。在合并数据集，rs2858996 GG（n=148）、GT（n=82）和 TT（n=12）基因型的最大 ALT 值中位数（25-75 分位数）分别为 1.2（0.7-1.9）、1.1（0.8-2.5）和 5.4（1.9-7.6）×ULN。所有 12 例 TT 患者的最大 ALT>ULN，8 例（67%）的 ALT≥3×ULN。与其他基因型相比，TT 基因型的 ALT≥3×ULN 的比值比（95%CI）为 39.7（2.2-703.7）。作为 ALT≥3×ULN 的预测因子，TT 基因型的阴性预测值为 0.83，阳性预测值为 0.67。没有 TT 患者发生肝衰竭。
HFE 基因中的 rs2858996/rs707889 多态性可能与接受帕唑帕尼治疗的 RCC 患者的可逆性 ALT 升高有关。
